Chemo- and Regioselective Functionalization of Nortrilobolide: Application for Semisynthesis of the Natural Product 2‑Acetoxytrilobolide

The difference in reactivity of the hexaoxygenated natural product thapsigargin (<b>1</b>) and the pentaoxygenated nortrilobolide (<b>3</b>) was compared in order to develop a chemo- and regioselective method for the conversion of nortrilobolide (<b>3</b>) into the natural product 2-acetoxytrilobolide (<b>4</b>). For the first time, a stereoselective synthesis of 2-acetoxytrilobolide (<b>4</b>) is described, which involves two key reactions: the first chemical step was a one-pot substitution–oxidation reaction of an allylic ester into its corresponding α,β-unsaturated ketone. The second process consisted of a stereoselective α′-acyloxylation of the key intermediate α,β-unsaturated ketone to afford its corresponding acetoxyketone, which was converted into 2-acetoxytrilobolide (<b>4</b>) in a few steps. This innovative approach would allow the synthesis of a broad library of novel and valuable penta- and hexaoxygenated guaianolides as potential anticancer agents